Growth arrest-specific gene 6 (Gas6) levels are elevated in patients with chronic renal failure

Lee, Iris J.; Hilliard, Brendan; Swami, Abhishek; Madara, John; Rao, Swati; Patel, Tapan; Gaughan, John; Lee, Jean; Gadegbeku, Crystal A.; Choi, Eric T.; Cohen, Philip L.

doi:10.1093/ndt/gfs337

Cited by 50 publications

(43 citation statements)

References 44 publications

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“…We confirmed higher values of both GAS6 and sMerTK in patients with renal failure. In accordance with these findings, higher values of GAS6 have been reported in chronic renal failure [33]. The sMerTK values seem linked to kidney disease, as the increase was mainly in patients with renal failure.…”

Section: Discussionsupporting

confidence: 72%

Vitamin K-dependent proteins GAS6 and Protein S and TAM receptors in patients of systemic lupus erythematosus: correlation with common genetic variants and disease activity

et al. 2013

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IntroductionGrowth arrest-specific gene 6 protein (GAS6) and protein S (ProS) are vitamin K-dependent proteins present in plasma with important regulatory functions in systems of response and repair to damage. They interact with receptor tyrosine kinases of the Tyro3, Axl and MerTK receptor tyrosine kinase (TAM) family, involved in apoptotic cell clearance (efferocytosis) and regulation of the innate immunity. TAM-deficient mice show spontaneous lupus-like symptoms. Here we tested the genetic profile and plasma levels of components of the system in patients with systemic lupus erythematosus (SLE), and compare them with a control healthy population.MethodsFifty SLE patients and 50 healthy controls with matched age, gender and from the same geographic area were compared. Genetic analysis was performed in GAS6 and the TAM receptor genes on SNPs previously identified. The concentrations of GAS6, total and free ProS, and the soluble forms of the three TAM receptors (sAxl, sMerTK and sTyro3) were measured in plasma from these samples.ResultsPlasma concentrations of GAS6 were higher and, total and free ProS were lower in the SLE patients compared to controls, even when patients on oral anticoagulant treatment were discarded. Those parameters correlated with SLE disease activity index (SLEDAI) score, GAS6 being higher in the most severe cases, while free and total ProS were lower. All 3 soluble receptors increased its concentration in plasma of lupus patients.ConclusionsThe present study highlights that the GAS6/ProS-TAM system correlates in several ways with disease activity in SLE. We show here that this correlation is affected by common polymorphisms in the genes of the system. These findings underscore the importance of mechanism of regulatory control of innate immunity in the pathology of SLE.

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Section: Discussionsupporting

confidence: 72%

Vitamin K-dependent proteins GAS6 and Protein S and TAM receptors in patients of systemic lupus erythematosus: correlation with common genetic variants and disease activity

et al. 2013

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“…In vitro stimulation of vascular smooth muscle cells or immortalized human mesangial cells with AngII induced Gas6 and Axl expression via NADPH-oxidase 17 . A more recent clinical study 18 demonstrated that circulating Gas6 is associated with renal disease severity and Gas6 levels were inversely correlated with kidney function in patients with end-stage renal disease. Likewise, in recipient Axl−/− chimeras the increases in kidney Gas6 mRNA levels showed greater ROS in kidneys during early phase of DOCA-salt.…”

Section: Discussionmentioning

confidence: 99%

Role of Axl in Early Kidney Inflammation and Progression of Salt-Dependent Hypertension

et al. 2013

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The Gas6/Axl pathway regulates many cell functions and is implicated in hypertension. In this study we aimed to investigate the role of Axl in immune cells on initiation and progression of salt-dependent hypertension. Deoxycorticosterone-acetate (DOCA; 75mg/60days release) and salt hypertension was induced for 1week or 6weeks in Axl chimeras generated by bone marrow (BM) transplant to restrict Axl deficiency to hematopoietic or non-hematopoietic compartments. Depletion of Axl in hematopoietic cells (Axl−/− →Axl+/+) reduced (133±2mmHg) increase in systolic blood pressure (BP) compared to other Axl chimeras (~150mmHg) 1week after DOCA-salt. Urine protein and renal oxidative stress were lowest in Axl−/− →Axl+/+ at 1week after DOCA-salt. Compensatory increase in Gas6 in kidneys of recipient Axl−/− may affect kidney function and BP in early phase of hypertension. Flow cytometry on kidneys from Axl−/− →Axl+/+ showed increase in total leukocytes, B and dendritic cells and decrease in macrophages compared to Axl+/+ →Axl+/+. These immune changes were associated with decrease in pro-inflammatory gene expression, in particular interferon gamma. Systolic BP returned to baseline in Axl−/− →Axl+/+ and Axl−/− →Axl−/− but remained increased in Axl+/+ →Axl+/+ and Axl+/+ →Axl−/− chimeras after 6weeks of DOCA-salt. Vascular apoptosis was increased in the global Axl−/− chimeras in the late phase of hypertension. In summary, we found that expression of Axl in hematopoietic cells is critical for kidney pathology in early phase of salt-dependent hypertension. However, Axl in both hematopoietic and non-hematopoietic lineages contributes to the late phase of hypertension.

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“…After informed consent, blood samples were collected from 6 healthy donors with normal kidney function and 20 patients with end-stage renal disease who were on hemodialysis (HD). Blood was collected prior to the routine HD session [30]. Blood samples were centrifuged at 3000 rpm, and the sera were aliquoted and stored at −80C.…”

Section: Methodsmentioning

confidence: 99%

Caspase-1 Plays a Critical Role in Accelerating Chronic Kidney Disease-Promoted Neointimal Hyperplasia in the Carotid Artery

Ferrer

Monroy

Lopez-Pastraña

et al. 2016

J. of Cardiovasc. Trans. Res.

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To determine whether caspase-1 is critical in chronic kidney disease (CKD)-mediated arterial neointimal hyperplasia (NH), we utilized caspase−/− mice and induced NH in carotid artery in a CKD environment, and uremic sera-stimulated human vascular smooth muscle cells (VSMC). We made the following findings: (1) Caspase-1 inhibition corrected uremic sera-mediated downregulation of VSMC contractile markers, (2) CKD-promoted NH was attenuated in caspase−/− mice, (3) CKD-mediated downregulation of contractile markers was rescued in caspase null mice, and (4) expression of VSMC migration molecule αvβ3 integrin was reduced in caspase−/− tissues. Our results suggested that caspase-1 pathway senses CKD metabolic danger signals. Further, CKD-mediated increase of contractile markers in VSMC and increased expression of VSMC migration molecule αvβ3 integrin in NH formation were caspase-1 dependent. Therefore, caspase-1 is a novel therapeutic target for the suppression of CKD-promoted NH.

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Growth arrest-specific gene 6 (Gas6) levels are elevated in patients with chronic renal failure

Cited by 50 publications

References 44 publications

Vitamin K-dependent proteins GAS6 and Protein S and TAM receptors in patients of systemic lupus erythematosus: correlation with common genetic variants and disease activity

Vitamin K-dependent proteins GAS6 and Protein S and TAM receptors in patients of systemic lupus erythematosus: correlation with common genetic variants and disease activity

Role of Axl in Early Kidney Inflammation and Progression of Salt-Dependent Hypertension

Caspase-1 Plays a Critical Role in Accelerating Chronic Kidney Disease-Promoted Neointimal Hyperplasia in the Carotid Artery

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